Over the last decade, the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against growth factor receptors, including the human epidermal growth factor receptors (HER1 and HER2) and drugs for hormone-receptor-positive disease. However, despite such encouraging results, patients that are initially responsive to these drugs eventually become resistant within one year of therapy. Multiple mechanisms responsible for resistance have been proposed, including compensatory crosstalk with alternate receptor tyrosine kinases (i.e. HER1-4, IGF-1R), hyper-activation of downstream MAPK-PI3K/Akt/mTOR signaling, activation of the inhibitor of apoptotic proteins (IAPs) and inactivation of PTEN and p53. We have identified soluble E-cadherin (sEcad) as a novel therapeutic target and have developed monoclonal antibodies targeting sEcad as an innovative therapy that directly kills cancer cells, spares normal cells and overcomes these host resistance pathways. Therefore, in this grant application we propose to first narrow down which HER or non-HER receptors (or combinations) are involved in the efficacy of our antibody- based therapy. We then will test whether combinatorial strategies involving HER or non-HER inhibitors, that act via different mechanism(s) of action than our antibody, may act additively or synergistically to suppress tumor growth and dissect some of the mechanism(s) involved. Lastly, we propose to complement our antibody with a panel of PD markers so as to ensure that the antibody is exerting its intended biologic outcome and perform preliminary studies to confirm no off-target effects. Altogether, we believe that our innovative therapy will make substantial strides in cure rates and in progression-free survival of patients with HER and non-HER-positive breast cancers that progress beyond targeted or other conventional therapies.